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Pediatric Surgery International

, Volume 27, Issue 6, pp 573–577 | Cite as

Prenatal administration of retinoic acid upregulates connective tissue growth factor in the nitrofen CDH model

  • Elke Maria Ruttenstock
  • Takashi Doi
  • Jens Dingemann
  • Prem Puri
Original Article

Abstract

Purpose

Recent studies have suggested that retinoids may be involved in the molecular mechanisms of pulmonary hypoplasia (PH) in congenital diaphragmatic hernia (CDH). Connective tissue growth factor (CTGF) plays a key role in foetal lung development and remodelling during later gestation. CTGF knockout mice exhibit PH with similar characteristics to the human and nitrofen-induced PH. Prenatal administration of retinoic acid (RA) has been shown to stimulate alveologenesis in nitrofen-induced PH. In vitro studies have revealed that RA can induce CTGF gene expression. We hypothesized that pulmonary gene expression of CTGF is downregulated during the later stages of lung development, and that prenatal administration of RA upregulates CTGF in the nitrofen CDH model.

Methods

Pregnant rats were exposed to either olive oil or nitrofen on day 9 (D9) of gestation. RA was given intraperitoneally on D18, D19 and D20. Foetuses were harvested on D21 and divided into control, CDH, control + RA and CDH + RA group. Pulmonary CTGF gene and protein expression levels were determined using RT-PCR and immunohistochemistry.

Results

On D21, CTGF relative mRNA expression levels were significantly downregulated in CDH group compared to controls. After RA treatment, expression levels of CTGF were significantly upregulated in CDH + RA and control + RA compared to the CDH group. Immunohistochemical studies confirmed these results.

Conclusion

Downregulation of pulmonary CTGF gene and protein expression during later stages of lung development may interfere with normal alveologenesis in the nitrofen CDH model. Upregulation of CTGF pulmonary gene expression after prenatal RA treatment may promote lung growth by promoting alveologenesis in the nitrofen-induced CDH model.

Keywords

Nitrofen Pulmonary hypoplasia (PH) Congenital diaphragmatic hernia (CDH) Retinoic acid (RA) Connective tissue growth factor (CTGF) 

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Elke Maria Ruttenstock
    • 1
  • Takashi Doi
    • 1
    • 2
  • Jens Dingemann
    • 1
  • Prem Puri
    • 1
    • 2
  1. 1.National Children’s Research CentreOur Lady’s Children’s HospitalDublin 12Ireland
  2. 2.School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical ResearchUniversity College DublinDublinIreland

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